G-protein coupled receptors (GPCRs) are among the most intensely investigated drug targets in the pharmaceutical industry. Over 40% of all FDA approved drugs target these important receptor proteins. Unfortunately, many of the ligands that are used as drugs or pharmacological tools are not selective and exhibit some unintended activity on non-target GPCRs or other proteins. This is because the orthosteric binding site is highly conserved among closely related types of GPCRs.
Dopamine receptors (DARs) belong to a large superfamily of neurotransmitter and hormone receptors. Five functionally active DARs have been identified in the mammalian genome. D1-like DARs (D1 and D5) are Gαs coupled, and D2-like DARs (D2, D3 and D4) are Gαi/o coupled. There are two isoforms of the D2 DAR, short and long (D2S and D2L), respectively, which are derived from alternative RNA splicing and vary in the size of their third intracellular loops. The D2L isoform is more prevalent, although both isoforms appear to be functionally similar. Amongst the DARs, the D2 DAR is arguably one of the most validated drug targets in neurology and psychiatry. For instance, all receptor-based anti-Parkinsonian drugs work via stimulating the D2 DAR (although controversy exists for a minor role of the D1 DAR), whereas all FDA approved antipsychotic agents are antagonists of this receptor. The D2 DAR is also therapeutically targeted in other disorders such as restless legs syndrome, tardive dyskinesia, Tourette's syndrome, psychosis, bipolar disorder, schizophrenia, and hyperprolactinemia. Most drugs targeting the D2 DAR (orthosteric agonists and antagonists) are problematic, either by being less efficacious than desired or possessing limiting side effects, most of which are due to off-target cross-GPCR reactivity. It is thus desirable to develop a class of novel therapeutic agents with high selectivity for the D2 DAR.
It should be noted that though the therapeutic potential for more selective D2 DAR antagonists may be enormous, this approach may also provide a way forward for developing selective pharmacological probes. Amongst the D2-like family of DARs (D2, D3, and D4), only the D4 DAR has ligands (both agonists and antagonists) that are truly specific, approaching 1,000 fold-selectively versus D2 and D3 DARs. This is not surprising given that the D4 DAR is more structurally divergent compared to the D2/D3 DARs. D2 and D3 receptors share 78% homology in their transmembrane spanning domains, which harbor the ligand binding sites and thus the pharmacologic properties between these two receptor subtypes are quite similar. Therefore, it is very challenging to identify small molecules that can selectively bind to and/or functionally modulate either D2 or D3 DAR receptor subtypes. A high level of probe selectivity will allow for definitive in vivo studies of receptor function. With respect to the D3 DAR, there are several compounds that exhibit good selectivity versus the D4 DAR and moderate (a few hundred fold) selectivity versus the D2 DAR. Some of these D3-selective compounds have been used for in vivo experiments but the results have been controversial in many instances. In contrast, to the best of our knowledge, there are only few series of compounds that exhibit even moderate selectivity for the D2 DAR receptor versus D3 and D4 within the D2-like DAR subfamily. Selective antagonists of the D2 DAR are useful for treatment of disorders currently treated with relatively non-selective D2 antagonists, including Tourette's syndrome, tardive dyskinesia, Huntington's chorea, psychosis, bipolar disorder, depression, and schizophrenia.
Patients suffering from schizophrenia comprise the largest patient population that would benefit from highly selective D2 DAR antagonists. Schizophrenia is characterized by delusions, hallucinations, social withdrawal, attention, and cognitive defects. All current FDA-approved antipsychotic drugs have D2 DAR blocking properties. It is likely that D2 DAR antagonism will remain a mainstay for the treatment of psychosis, especially for the treatment of so-called “positive” symptoms of this illness. Unfortunately, all antipsychotic drugs that antagonize D2 DARs also interact with other GPCRs to varying degrees, including adrenergic, serotonergic, histaminergic, and cholinergic receptors. It is therefore not surprising that such drugs have multiple adverse effects including sedative, extra-pyramidal, endocrine, metabolic, and hypotensive properties. Because of the lack of highly selective ligands, it is not known to what extent other GPCRs contribute to the antipsychotic actions and/or associated side effects of these agents, although the H1 histamine receptor has been implicated in weight gain.
The present disclosure fulfills the need for highly selective D2 DAR compounds and also provides additional advantages.